The aim of the proposed work is to explore the nature of cues used by optic axons to find appropriate targets in the mammalian brain. The relationship between the location of a neuron and its ability for target-directed axonal outgrowth will be explored by analyzing the projections from embryonic retinae grafted into the brainstems of newborn animals. Previously, a xenogeneic transplantation paradigm was developed in which mouse retinae are grafted into rat brains and their projections subsequently traced using mouse- specific monoclonal antibodies (directed against neuronal cell- surfaces). The proposed experiments will use these technologies to study two classes of cues: (i) those restricted to the outer surfaces of the brain, and (ii) those independent of the brain surfaces, which arise from the target region. The proposal consists of four interrelated in vivo experiments. The first will examine the patterns of axonal outgrowth from the time the projection, are first detectable. The second will examine, using light and electron microscopy, the cellular substrates utilized by retinal efferents. The third will determine the distance over which the target region influences directed axonal outgrowth. The fourth will use "eyeless" mutant mice to investigate the ability of a virgin target to support optic axon outgrowth and innervation. There are several broad objectives of these studies. First, this work will establish in vivo correlates for those axonal guidance substrates defined in vitro. In addition, these neural grafting studies address the issues of how the specificity of connections is established during development and later maintained in the mammalian CNS. Second, they provide a neuroanatomical complement to work in progress which has shown that grafted neural tissue can integrate with and function in a neural pathway. Finally, it is important that these aspects of CNS development be addressed in vivo since they are likely to be essential in understanding congenital neural defects and in designing strategies to restore functional neural circuits.